title: Plasma from a case of recurrent idiopathic FSGS perturbs non-muscle myosin IIA (MYH9 protein) in human podocytes.
abstract: The MYH9 gene encodes a non-muscle myosin IIA heavy chain (NMMHC-IIA) expressed in podocytes. Heterozygous MYH9 mutations cause a set of overlapping syndromes characterized by variable degrees of deafness, morphologic abnormalities of platelets and focal segmental glomerulosclerosis (FSGS) with progressive renal dysfunction. Similar glomerular lesions are seen in a variety of nephropathies, including an idiopathic form of FSGS in children which recurs in renal allografts, implying a circulating factor that affects glomerular podocyte biology. It is unknown whether NMMHC-IIA is perturbed in the idiopathic form of FSGS. We describe a pediatric patient with typical idiopathic FSGS, in whom proteinuria recurred within hours of deceased donor renal transplantation but who responded to plasmapheresis. We demonstrate in vitro that plasmapheresis effluent from our patient rapidly decreased cultured podocyte levels of the phosphorylated myosin light chain (MLC) that mediates NMMHC-IIA binding to actin and induced dispersion of NMMHC-IIA from its usual position along actin stress fibers. FSGS plasma also caused dispersion of slit diaphragm proteins (nephrin and podocin) and vinculin-positive focal adhesion complexes. Our observations suggest that the putative circulating factor in idiopathic FSGS disrupts normal NMMHC-IIA function in podocytes and might contribute to the pathogenesis of recurrent FSGS in other children.
authors.affiliation: Department of Medicine, McGill University, 3775 University Street, Montreal, QC, H3A2B4, Canada.
authors.forename: Sima
authors.initials: S
authors.lastname: Babayeva
authors.forename: Michelle
authors.initials: M
authors.lastname: Miller
authors.forename: Yulia
authors.initials: Y
authors.lastname: Zilber
authors.forename: Reyhan
authors.initials: R
authors.lastname: El Kares
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernard
authors.forename: Martin
authors.initials: M
authors.lastname: Bitzan
authors.forename: Paul
authors.initials: P
authors.lastname: Goodyer
authors.forename: Elena
authors.initials: E
authors.lastname: Torban
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D002460:Cell Line; D048429:Cell Size; D002648:Child; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood* / Q000473:pathology / Q000601:surgery; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000097:blood; D016030:Kidney Transplantation; D008565:Membrane Proteins / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D010956:Plasmapheresis; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D011507:Proteinuria / Q000097:blood; D012008:Recurrence; D022502:Stress Fibers / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C103814:MYH9 protein, human; D008565:Membrane Proteins; D020409:Molecular Motor Proteins; D018994:Myosin Light Chains; C407223:NPHS2 protein; C113267:nephrin; D018995:Myosin Heavy Chains